Digitalis glycosides are indispensible in the treatment of congestive heart failure, but they are very toxic. The objective of the proposed research is to study the relationship of C(17)-side group geometry to biological activity. Collaborative research of the applicants has revealed that cardenolide activity is very responsive to subtle configurational and conformational changes in the side group. The proposed research seeks to delineate this relationship. The overall project includes synthesis, biological studies (done at the Univ. Minnesota), crystallographic studies (done at the Medical Foundation of Buffalo, NY) and conformational energy studies (done primarily at Buffalo, but some at Oregon State University).